CN1128989A - N-substituted azaheterocylic carboxylic acid and esters thereof - Google Patents
N-substituted azaheterocylic carboxylic acid and esters thereof Download PDFInfo
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- CN1128989A CN1128989A CN94193058A CN94193058A CN1128989A CN 1128989 A CN1128989 A CN 1128989A CN 94193058 A CN94193058 A CN 94193058A CN 94193058 A CN94193058 A CN 94193058A CN 1128989 A CN1128989 A CN 1128989A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The present invention relates to therapeutically active azaheterocyclic compounds of formula (I) wherein A is (a), (b) or (c), a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in treating a central nervous system ailment related to the GABA uptake.
Description
Invention field
The present invention relates to azaheterocyclic carboxylic acid and ester thereof that novel N-replaces, wherein-bar has the alkyl chain of replacement to form the integral part of this N-substituting group and salt thereof, relate to its preparation method, relate to the composition that contains this compounds, and the purposes aspect the dysfunction of clinical treatment γ-An Jidingsuan nerve conduction system.
Background of invention
In recent years, transmit matter, carried out a large amount of pharmaceutical researches about the inhibitory nerve in this mammalian central nervous system of γ-An Jidingsuan (hereinafter to be referred as GABA).
The inhibition of GABA picked-up causes this inhibitory nerve to transmit the availability raising of matter in synaptic cleft, thereby improves the activity (ergic activity) of GABA energy.GABA can active raising have the treatment of being beneficial to such as anxiety, pain and epilepsy, and muscle and ataxia (for example, consult P.Krogsgaard-Larsen et al., Progress inMedicinal Chemistry, 1985,22,68-112).
Enter from synaptic cleft pre-synapse nerve ending and spongiocyte GABA picked-up-kind of well-known and powerful inhibitor, be such as 3-piperidine carboxylic acid (nipecotic acid).Yet, owing to be a kind of suitable polar compound, thereby can not pass through blood brain barrier, 3-piperidine carboxylic acid itself can not be brought into play the actual utility as medicine.
In U.S. Patent No. 4,383,999 and No.4,514,414 and EP236342 and EP231996 in, the patent right of some derivatives of N-(4,4-two replacement-3-butenyls) azaheterocyclic carboxylic acid as the GABA uptake inhibitor proposed.In EP342635 and EP374801, proposed oxime ether and vinyl ether and constituted the patent right of the N-substituted heterocycle carboxylic acid of its N-substituting group integral part respectively as the GABA uptake inhibitor.In addition, in WO9107389 and WO9220658, the patent right of N-substituted azetidine carboxylic acid as the GABA uptake inhibitor proposed.EP221572 claims that 1-aryloxyalkyl group pyridine-3-carboxylic acid is the GABA uptake inhibitor.
According to Yunger, L.M.et al., J.Pharm.Exp.Ther., 1984,228,109, (4,4-phenylbenzene-3-butene-1-yl) nipecotic acid (is named as SK﹠amp to N-; F89976A), (4,4-phenylbenzene-3-butene-1-yl) guvacine (is named as SK﹠amp to N-; F100330A), (4,4-phenylbenzene-3-butene-1-yl) height-β-proline(Pro) (is named as SK﹠amp to N-; F100561) and N-(4-phenyl-4-(2-thienyl)-the 3-butene-1-yl) nipecotic acid (is named as SK﹠amp; F100604J) be the active GABA uptake inhibitor of per os.These data have been incorporated into Krogsgaard-Larsen, P.et al., Epilepsy Res., 1987,1,77-93.
Invention is described
The present invention relates to novel N-substituted azetidine carboxylic acid and ester thereof, its general formula (I) is:
Wherein A is:
Wherein:
R
1Be saturated or unsaturated 5 yuan or 6 yuan of carbocyclic rings, this carbocyclic ring can be randomly by the C of 1 or 2 halogens, straight or branched
1-4The C that alkyl, phenyl, phenyl replace
1-4The C that alkyl or phenyl replaces
2-4Alkenyl replaces, and described phenyl can be randomly by halogen, C
1-4Alkyl, C
1-4Alkoxyl group or trifluoromethyl replace, and these saturated or unsaturated 5 yuan or 6 yuan of carbocyclic rings can randomly condense with a phenyl ring;
R
2Be hydrogen, straight or branched C
1-8Alkyl, straight or branched C
2-8The C that alkenyl, phenyl, phenyl replace
1-4The C that alkyl or phenyl replaces
2-4Alkenyl, described phenyl can be randomly by halogen, C
1-4Alkyl, C
1-4Alkoxyl group or trifluoromethyl replace;
R
3And R
4Represent hydrogen separately or lump together and represent a key;
X is hydroxyl or C
1-4Alkoxyl group;
N is 0,1 or 2;
M is 2,3 or 4;
Its condition is: when A is
The time, R
1And R
2Must not be simultaneously for randomly by halogen, C
1-4Alkyl, C
1-4The phenyl that alkoxyl group or trifluoromethyl replace, or its pharmaceutically acceptable salt.
The compound of general formula I can be used as geometrical isomer and optical isomer exists, and all isomer and composition thereof include within the scope of the present invention.Isomer can separate by means of the fractional crystallization of standard method such as chromatographic technique or suitable salt.
Can be from randomly existing according to compound of the present invention, or when hydroxy-acid group is not esterified, can accept metallic salt form on medicine and exist with pharmaceutically acceptable acid salt form, or exist with ammonium salts during randomly by alkylation.
The example of such salt comprises mineral acid and organic acid addition salt, for example hydrochloride, hydrobromate, vitriol, phosphoric acid salt, acetate, phthalate, fumarate, horse are hydrochlorate, Citrate trianion, lactic acid salt, tartrate, oxalate. or similar pharmaceutically acceptable mineral acid or organic acid addition salt, and comprise the Tournal ofPharmaceutical Science that classifies this paper reference as, listed pharmaceutically acceptable salt in 66,2 (1977).
In a better embodiment of the present invention, R
1C in the definition
1-4Alkyl is methyl or ethyl, at R
2In-the substituting group, C
1-8Alkyl is methyl, ethyl, propyl group, butyl or amyl group and isomer thereof, C
1-4Alkyl is methyl or ethyl, C
1-4Alkoxyl group is a methoxy or ethoxy, and X comprises methoxyl group, oxyethyl group, isopropoxy or positive propoxy, and n comprises 1 or 2, and m comprises 2 or 3.
Compound of Formula I has bigger lipophilicity than the substituent parent compound of no N-(being piperidine carboxylic acid and guvacine), thereby brain is had bigger validity.
Proving already, to having inhibiting general formula I novel cpd why to have useful pharmacological property central nervous system from synaptic cleft picked-up GABA, is because they cause that the active selectivity of energy of GABA strengthens.Compound of Formula I can be used for treatment such as pain, anxiety, the dyskinesia of the too much property of pyrimidine, epilepsy and some muscle and ataxia.They also can be used as tranquilizer, soporific and thymoleptic.
Compound of Formula I prepares with the following method:
Method A:
The compound of general formula I I, in the formula definition of A, n and m the same, and Y is a suitable leavings group such as halogen, tosic acid root or methanesulfonate, can with the nitrogen heterocyclic reaction of general formula III, R in the formula
3, R
4The same with the definition of X.This alkylated reaction can be in a kind of solvent such as acetone, dibutyl ether, 2-butanone, tetrahydrofuran (THF), methyl iso-butyl ketone (MIBK), isopropyl acetate or toluene, in the presence of a kind of alkali such as salt of wormwood and a kind of catalyzer such as alkaline metal iodide, can carry out such as 1～120 hour up to the temperature of the reflux temperature of solvent for use.
Method B:
Wherein A and n general formula I V compound as defined above can with R wherein
3, R
4, m and X as defined above, and Z is the general formula V compound reaction of a suitable leavings group such as halogen, tosic acid root or methanesulfonate.This alkylated reaction can be in a kind of suitable solvents such as dibutyl ether, 2-butanone, tetrahydrofuran (THF), methyl iso-butyl ketone (MIBK) or toluene, in the presence of a kind of alkali such as salt of wormwood or sodium hydride, under can temperature, carry out such as 1～120 hour up to the reflux temperature of solvent for use.
The compound of general formula I I, III and IV can easily prepare with the method that the person skilled in the art was familiar with.The compound of general formula V can be according to the step preparation of describing among the EP374801.
In some cases, have the suitable blocking group of necessary usefulness and protect the intermediate that uses in the above method, as the compound of general formula III or V.For example, can make this hydroxy-acid group esterification.The introduction of such group and remove and see " Protective Groups in OrganicSynthesis ", T.W.Greene and P.G.M.Wuts, 2ed. (John Wiley, 1991) for details.
Pharmacological method
The compounds of this invention [
3H]-the stripped inhibiting value of GABA picked-up be basically with Fjalland method (Acta Pharmacol.Toxicol.1978,42,73-76) estimate.
Male Wistar crystallographic system rat cortex tissue is with one table glass/PTFE homogenizer, with the 0.32M sucrose of 10 times of volumes, with the hand homogenize that blows slowly.With a kind of 120nM NaCl, 9.2nM KCl, 4mM MgSO of containing
4, 2.3nM CaCl
2Cultivated 60 minutes at 30 ℃ with the 40mMTRIS HCl buffer reagent (30 ℃ of pH7.5) of 10mM glucose.
Table 1 has been listed the GABA picked-up inhibiting value of some representative compounds.
Table 1
[
3H]-GABA absorbs inhibiting value
| Instance number | IC exsomatizes 50(μM) |
| ????1 ????2 ????3 ????4 ????5 ????6 ????7 ????8 ????9 ???10 ???11 | ??????4500 ???????325 ??????6400 ???????338 ???????495 ??????2000 ???????263 ???????150 ???????100 ????＞3000 ???????113 |
For above indicator value, dosage will be different because of compound of Formula I, administering mode and the desirable treatment adopted.Yet in general, the dosage that can obtain gratifying result is about 0.5mg～about 1000mg, better about 1mg～about 500mg compound of Formula I, and administration every day is 1～5 time easily, randomly with the slowly-releasing form.Usually, be applicable to that peroral administration dosage form comprises and about 0.5mg～about 1000mg of pharmaceutical carrier or thinner fusion, better about 1mg～about 500mg compound of Formula I.
Compound of Formula I can be with pharmaceutically acceptable acid salt form, or under possible situation with metal-salt or the administration of low alkyl group ammonium salts.
The present invention also relates to contain the pharmaceutical composition of compound of Formula I or its pharmaceutically acceptable salt, and such composition also contains pharmaceutical carrier or thinner usually.The composition that contains The compounds of this invention can prepare with common technology, and is common type, for example capsule, tablet, solution or suspension.
The pharmaceutical carrier that adopts can be solid carrier commonly used or liquid vehicle.The example of solid carrier is lactose, carclazyte, sucrose, talcum powder, gelatin, agar, pectin, gum arabic, Magnesium Stearate and stearic acid.The reality of liquid vehicle is not syrup, peanut oil, sweet oil and water.
Similarly, carrier or thinner can comprise any technical known time-delay material, and for example, glyceryl monostearate or glyceryl SUNSOFT Q-182S are mixed use separately or with wax.
If use the solid carrier of oral administration, then said preparation can be made into tablet, puts in the hard capsule glue with powder or piller form, also can be made into lozenge or lozenge form.The usage variance of solid carrier is very big, but will be about 25mg usually～about 1g.If the use liquid vehicle, then said preparation can be made into syrup, emulsion, soft capsule or sterile injectable liquid such as water or forms such as on-aqueous liquid suspension or solution.
In general, compound of the present invention is mixed with presented in unit dosage form, and every dosage unit comprises 50～200mg active ingredient or contains pharmaceutically acceptable carrier simultaneously.
According to the dosage of compound of the present invention, when during to patient such as people's administration, being 1～500mg/ day with medicament forms, for example, every dose of about 100mg.
A kind of can comprising by the typical tablet of pressed disc technique preparation commonly used:
Label:
Active compound (free cpds or its salt) 100mg
Colloid silica (Aerosil
) 1.5mg
Microcrystalline Cellulose (Avicel
) 70mg
Modified cellulose gum (Ac-Di-Sol
) 7.5mg
Magnesium Stearate
Dressing:
The about 9mg of HPMC
*Mywacett
The about 0.9mg of 9-40T
*The acidylate direactive glyceride is as the film coating softening agent.
Route of administration can be can effectively this active compound be transported to suitably or any approach at predictive role position, per os or non-for example through intestines, as per rectum, through skin, through subcutaneous, through intravenously, in intramuscular or intranasal, better be the per os approach.
Example
Following example further specifies the preparation method of compound of Formula I, yet it is not interpreted as restriction.
Hereinafter, TLC is a tlc, and THF is a tetrahydrofuran (THF), CDCl
3Be the deuterate chloroform, DMSO-d
6Be six deuterium dimethyl sulfoxide (DMSO).The structure of these compounds or confirm with elemental microanalysis method or with NMR (nuclear magnetic resonance method) in the case, as long as suitably, is just listed the peak of feature proton correspondence in the title compound.NMR displacement (δ) is represented with ppm.M.p. be fusing point, with ℃ representing.Column chromatography is with W.C.Still et al., J.Org.Chem., and 1978,43, the described technology of 2923-2925 (Art.9385) is carried out with Merck silica gel 60.As the compound or the known compound of starting raw material, or the compound that can easily prepare with known method own.
Example 1
1-(2-(3-phenyl-1-propoxy-) ethyl)-3-piperidine carboxylic acid hydrochloride
Sodium hydride (1.5g, 37mmol, 60% oil suspension) joined in batches place the 3-that the stirring phenyl-1-propyl alcohol of nitrogen under enclosing (5.0g is in toluene 37mmol) (25ml) solution.This mixture at room temperature stirred 30 minutes, and reflux is 45 minutes then.Allow reaction mixture cool off, add another part sodium hydride (1.5g, 37mmol, 60% oil suspension) again, then add toluene (25ml).With its cooling of relief in 15 minutes of this suspension reflux.Keep temperature to be lower than adding under 40 ℃ the condition in batches 1-(2-bromotrifluoromethane)-3-piperidine carboxylate hydrobromate (12.6g, 37mmol, EP374801).Reaction mixture was stirred 3 days, placed for 3 weeks then.Mixture is poured in the water (200ml), with ethyl acetate (100ml) extraction.Two be separated after, organic phase with 5% citric acid solution (3 * 100ml) extraction.The organic phase that merges discards organic phase with ethyl acetate (100ml) extraction.Add 4N sodium hydroxide at aqueous phase and reach 8, use ethyl acetate (2 * 100ml) extractions then up to the pH value.The organic extract that merges washs with saturated sodium bicarbonate solution, uses Na then
2SO
4Dry.After removing solvent, vacuum-evaporation obtains 3.2g oily 1-(2-(3-phenyl-1-propoxy-) ethyl)-3-piperidine carboxylic acid hydrochloride ethyl ester.
(3.2g 10mmol) is dissolved in the ethanol (10ml), adds 12N sodium hydroxide (2.5ml) then with top ester.This mixture at room temperature stirred 3 hours.Add excessive concentrated hydrochloric acid then, then add methylene dichloride (300ml).Mixture Na
2SO
4Drying, solvent be through vacuum-evaporation, and the residue that obtains is with twice of acetone revaporization.Residue acetoneand ethyl acetate crystallization is then used acetone recrystallization, obtains 1.1g solid title compound.M.p.115-117 ℃. calculated value C
17H
25NO
3HCl1/2H
2O:C, 60.6%; H, 8.1%; N, 4.2%: measured value: C, 60.7%; H, 8.1%:N, 3.9%.
Example 2
(R)-1-(2-(2-benzyl benzyloxy) ethyl)-3-piperidine carboxylic acid hydrochloride
Sodium hydride (2.1g, 53mmol, 60% oil suspension) joined in batches place the 2-benzyl benzyl alcohol that stirring of nitrogen under enclosing (5.0g is in anhydrous THF (125ml) solution 25mmol).This mixture heating up was refluxed 1 hour, in 30 minutes, allow its cool to room temperature then.(EP374801), mixture at room temperature stirred 2 days for 8.6g, 25mmol to add Hydrogen bromide (R)-1-(2-bromotrifluoromethane)-3-piperidine carboxylate.Reaction mixture dilutes after-filtration with THF (100ml).Vacuum-evaporation removes the oily residue that obtains behind the solvent and goes up purification with column chromatography at silica gel (700g, heptane/ethyl acetate=1/1), obtains 0.8g (R)-1-(2-(2-benzyl benzyloxy) ethyl)-3-piperidine carboxylic acid hydrochloride ethyl ester oily matter.
(0.8g 2.1mmol) is dissolved in the ethanol (10ml), adds 2N sodium hydroxide (3.1ml) then with top ester.This mixture at room temperature stirs and spends the night.Add excessive concentrated hydrochloric acid, then add methylene dichloride.Mixture adds entry behind vacuum concentration and methylene dichloride is separated two, organic phase MgSO
4Dry.Solvent is through vacuum-evaporation, and the spumescence residue that obtains obtains 0.65g amorphous solid title compound with the methylene dichloride revaporization.
1H NMR (DMSO-d
6) δ 3.83 (brs, 2H); 4.03 (s, 2H); 4.53 (s, 2H). calculated value C
22H
27NO
3HCl:C, 67.8%; H, 7.2%; N, 3.6%; Measured value: C, 68.2%; H, 7.5%; N, 3.4%.
Example 3
(R)-1-(2-((1-phenyl-2-naphthyl) methoxyl group) ethyl)-3-piperidine carboxylic acid hydrochloride
(10ml, 10mmol) solution places nitrogen to enclose down, splashes into anhydrous THF (10ml) solution of 1-phenyl-2-naphthoic acid (Synthesis 1983,105 for 2.4g, 10mmol) then with the THF of the lithium aluminium hydride of 1.0M.After dropwising mixture was at room temperature stirred 30 minutes, under refluxing, stirred 30 minutes again.Allow after the reaction mixture cooling, add entry (0.4ml), 4N sodium hydroxide (0.4ml) and water (1.2ml) successively carefully.Mixture dilutes, filters then with diethyl ether after 30 minutes in stirring at room.Vacuum-evaporation is dissolved in residue in the toluene after removing solvent.Use MgSO
4Dry, again remove through vacuum-evaporation obtain thick (1-the phenyl)-2-naphthyl of 2.3g after desolvating) methyl alcohol.
Top alcohol (2.3g) is dissolved in the toluene (10ml), adds thionyl bromide (1.0ml) mixture and at room temperature stirred 1 hour, reflux 10 minutes at room temperature stirred 30 minutes at last.Reaction mixture with the washing of 10% sodium hydrogen carbonate solution, is used MgSO with toluene (75ml) dilution then
4Dry.After removing solvent, vacuum-evaporation obtains thick (1-phenyl-2-naphthyl) monobromomethane.
To not have water glycol (20ml) and place on the ice bath of nitrogen under enclosing, splash into hexane (6.0ml) solution of 2.5M n-Butyl Lithium.After dropwising mixture was stirred 15 minutes, add the above-mentioned thick bromide that is dissolved in the hexanaphthene (5ml).Reaction mixture was at room temperature stirred 2 days, and water (50ml) dilution then is with diethyl ether (100ml) extraction.Organic phase washes with water, dry (MgSO
4), vacuum-evaporation removes solvent.Residue is gone up at silica gel (100g, heptane/ethyl acetate=3/2) with column chromatography and is purified, and obtains 2.3g2-((1-phenyl-3-naphthyl) methoxyl group) ethanol oily matter.
Triethylamine (2.9ml) is joined the above-mentioned alcohol that is stirring, and (2.3g is in ether 8.3mmol) (50ml) solution.Anhydrous diethyl ether (10ml) solution that dropwise adds methylsulfonyl chloride (0.96ml).After dropwising mixture was stirred 90 minutes, add entry (20ml) then.Be separated two, with the organic phase drying.The thick methylsulfonyl thing that obtains after vacuum-evaporation removes solvent is dissolved in the acetone (50ml).Add (R)-3-piperidine carboxylate tartrate (3.8g, 12.4mmol) and salt of wormwood (2.9g, 21mmol), with reaction mixture reflux 4 days.Cooled mixture is filtered, the residue that obtains after vacuum-evaporation removes solvent uses column chromatography at silica gel (150g, heptane/ethyl acetate=1/1) goes up purification, obtain 3.0g (R)-1-(2-((1-phenyl-3-naphthyl) methoxyl group) ethyl)-3-piperidine carboxylate oily matter.
(3.0g 7.2mmol) is dissolved in the ethanol (20ml), adds 4N sodium hydroxide (5.4ml) then with top ester.This mixture at room temperature stirred 3 hours.Add concentrated hydrochloric acid (2.4ml), then add methylene dichloride (300ml).Use MgSO
4Drying, solvent is through vacuum-evaporation.Residue obtains 2.5g solid title compound with the acetone revaporization.M.p.153-155 ℃. calculated value C
25H
27NO
3HCl:C, 70.5%; H, 6.6%; N, 3.3%; Measured value: C, 70.1%; H, 6.7%; N, 3.1%.
Example 4
(R)-1-(2-(2-phenyl benzyloxy) ethyl)-3-piperidine carboxylic acid hydrochloride
(5.0g 25mmol) joins in batches and places the lithium aluminium hydride of nitrogen under enclosing (1.0g is 25mmol) in the mixture in anhydrous THF (25ml) with the 2-diphenic acid.After interpolation finishes, mixture was at room temperature stirred 30 minutes, under refluxing, stirred 30 minutes then.Allow reaction mixture cool off, carefully add entry (1.0ml), 4N sodium hydroxide (1.0ml) and water (3.0ml) successively.Mixture is separated two with ether (50ml) dilution.Organic phase MgSO
4Drying, vacuum-evaporation removes solvent, residue toluene coevaporation.The careful thionyl chloride (5ml) that adds at room temperature stirred this mixture 1 hour then in gained oily residue.Remove excessive thionyl chloride under vacuum, the residue that obtains is dissolved in the toluene.This organic solution with 10% sodium bicarbonate wash, drying.Behind the vacuum removal solvent, obtain the thick 2-xenyl of 4.0g methyl chloride.
Hexane (10ml) drips of solution of 2.5M n-Butyl Lithium is added to places nitrogen to enclose no water glycol (20ml) on the ice bath down.After dropwising mixture was stirred 30 minutes, add above-mentioned thick muriate.Reaction mixture at room temperature stirred 4 days, and extracted with diethyl ether is used in water (100ml) dilution.Organic phase washes with water, dry (MgSO
4), vacuum-evaporation removes and desolvates.Residue is gone up at silica gel (200g, heptane/ethyl acetate=3/2) with column chromatography and is purified, and obtains 2.2g 2-(2-phenyl benzyloxy) ethanol oily matter.
(2.2g, anhydrous THF (20ml) solution 10mmol) place on the ice bath of nitrogen under enclosing, and (4.0ml, 10mmol) solution stir mixture 15 minutes after dropwising to the hexane that wherein splashes into the 2.5M n-Butyl Lithium with above-mentioned alcohol.(1.1g 10mmol), removes ice bath, and mixture was at room temperature stirred 2 hours to add methylsulfonyl chloride.Vaporising under vacuum is removed volatile matter, add acetone (50ml), (R)-3-piperidine carboxylate tartrate (4.6g, 15mmol) and salt of wormwood (3.5g, 25mmol).This mixture heating up was refluxed 6 days cooled and filtered.Vacuum-evaporation removes the residue that obtains behind the solvent and goes up purification with column chromatography at silica gel (200g, heptane/ethyl acetate=3/2), obtains 1.9g (R)-1-(2-(2-phenyl benzyloxy) ethyl)-3-piperidine carboxylate oily matter.
(1.9g 5.2mmol) is dissolved in the ethanol (15ml), adds 4N sodium hydroxide (3.9ml) then with top ester.This mixture at room temperature stirred 2 hours, added concentrated hydrochloric acid (2ml) then, then added methylene dichloride (250ml).Be separated two, use MgSO after organic phase water (5ml) washing
4Drying, solvent is through vacuum-evaporation.Residue is used the acetone crystallization then with the acetone revaporization, obtains 1.3g solid title compound.M.p.148-149 ℃. calculated value C
21H
25NO
3HCl:C, 67.1%; H, 7.0%; N, 3.7%; Measured value: C, 67.2%; H, 7.0%; N, 3.4%.
Example 5
E-(R)-1-(2-((2,3-phenylbenzene-2-propylene-1-yl) oxygen) ethyl)-3-piperidine carboxylic acid hydrochloride
With 1,2-phenylbenzene-1-propylene (9.7g, 50mmol), N-bromosuccinimide (8.9g, 50mmol), the mixture heating up of dibenzoyl peroxide (0.1g) and tetrachloromethane (50ml) refluxed 21 hours.With the cold filtration of mixture, vacuum-evaporation removes the solvent in the filtrate, obtains 13.1g 3-bromo-1, and 2-phenylbenzene-1-propylene exists with E/Z isomer mixture form.
Place indifferent gas to enclose down ethylene glycol (40ml), be placed on and cool off on the ice bath, add hexane (23ml, 58mmol) solution of 2.5M n-Butyl Lithium then carefully.After at room temperature stirring 20 minutes, add the above-mentioned bromide that is dissolved in a small amount of hexanaphthene.Feeding nitrogen is removed hexanaphthene wherein in reaction mixture, continues then to stir 5 hours.Add entry (75ml), (3 * 75ml) extract mixture with ethyl acetate.The organic phase water (25ml) that merges washs, uses Na
2SO
4Dry.Vaporising under vacuum removes solvent, residue is gone up at silica gel (300g, normal heptane/ethyl acetate=7/3) with column chromatography and is purified, and obtains 6.2gZ-2-((2,3-phenylbenzene-2-propylene-1-yl) ethanol and 2.7gE-2-((2,3-phenylbenzene-2-propylene-1-yl) oxygen) ethanol oxygen).
(2.5g adds hexane (4.0ml, 10mmol) solution of 2.5M n-Butyl Lithium in anhydrous THF solution 10mmol) to above-mentioned E-alcohol at 0 ℃.Mixture stirred 10 minutes at 0 ℃, and (1.9g 10mmol), at room temperature stirred this mixture 1 hour then to add 4-Methyl benzenesulfonyl chlorine.Vacuum-evaporation is dissolved in residue in the acetone (25ml) after removing solvent, add (R)-3-piperidine carboxylate (2.4g, 15mmol) and salt of wormwood (2.5g, 18mmol).Mixture at room temperature stirred 7 days, filtered, and the solvent in the filtrate is removed in vacuum-evaporation, and residue is dissolved in the toluene (30ml), gained solution 1N hcl as extraction agent.Water transfers to 10 with solid carbonic acid potassium with pH with ethyl acetate (10ml) washing, uses ethyl acetate (3 * 50ml) extractions then.The ethyl acetate that merges is used Na mutually
2SO
4Drying, vacuum-evaporation obtain the thick ester of 1.0g after removing and desolvating.Toluene is mutually with the neutralization of 10% salt of wormwood, organic phase Na
2SO
4Dry.Vacuum-evaporation obtains the thick ester of other 4.3g after removing and desolvating.The crude product that merges is gone up at silica gel (150g, normal heptane/ethyl acetate=1: 1) with column chromatography and is purified, and obtains 1.45g E-(R)-1-(2-((2,3-phenylbenzene-2-propylene-1-yl) oxygen) ethyl)-3-piperidine carboxylate.
(1.45g 3.7mmol) is dissolved in the absolute ethanol (15ml), adds 4N sodium hydroxide (1.9ml) then with top ester.After at room temperature stirring 4 hours, mixture is with methylene dichloride (300ml) dilution, adds 4N hydrochloric acid (4ml) after being cooled to 0 ℃.Mixture Na
2SO
4Carry out vacuum-evaporation after the drying, desolvate to remove.Residue acetone coevaporation is suspended in the acetone (10ml), and the collecting precipitation thing at air drying, obtains 1.2g solid title compound with it.M.p.214-215 ℃. calculated value C
23H
27NO
3HCl:C, 68.7%; H, 7.0%; N, 3.5%; Measured value: C, 68.7%; H, 7.3%; N, 3.6%.
1H-NMR(DMSO-d
6)δ4.36(s，2H)；6.73(s，1H)。
Example 6
Z-(R)-1-(2-((2,3-phenylbenzene-2-propylene-1-yl) oxygen) ethyl)-3-piperidine carboxylic acid hydrochloride
At 0 ℃ of hexane (10.0ml, 24mmol) solution that in the Z-2-under indifferent gas encloses ((2,3-phenylbenzene-2-propylene-1-yl) oxygen) ethanol (6.0g, 24mmol prepare according to example 5) anhydrous THF solution, drips the 2.5M n-Butyl Lithium.Mixture stirred 10 minutes at 0 ℃, and (4.5g 24mmol), at room temperature continues to stir 1 hour to add 4-Methyl benzenesulfonyl chlorine.Vacuum-evaporation is dissolved in residue in the acetone (50ml) after removing solvent, add (R)-3-piperidine carboxylate (5.6g, 35mmol) and salt of wormwood (5.9g, 43mmol).Mixture at room temperature stirred 7 days, filtered, and the solvent in the filtrate is removed in vacuum-evaporation.Residue is dissolved in the toluene (70ml), and gained solution extracts with 1N hydrochloric acid (70ml).Water transfers to 10 with solid carbonic acid potassium with pH with ethyl acetate (20ml) washing, uses ethyl acetate (3 * 100ml) extractions then.Organic phase Na
2SO
4Drying, vacuum-evaporation obtain the thick ester of 3.2g after removing and desolvating.Toluene is mutually with the neutralization of 10% salt of wormwood, organic phase Na
2SO
4Dry.Vacuum-evaporation obtains the thick ester of other 12.3g after removing and desolvating.The crude product that merges is gone up at silica gel (300g, normal heptane/ethyl acetate=1: 1) with column chromatography and is purified, and obtains 5.7g Z-(R)-1-(2-((2,3-phenylbenzene-2-propylene-1-yl) oxygen) ethyl)-3-piperidine carboxylate.
(3.15g 8mmol) is dissolved in the absolute ethanol (25ml), adds 4N sodium hydroxide (4.0ml) then with top ester.After at room temperature stirring 4.5 hours, mixture is with methylene dichloride (400ml) dilution, adds 4N hydrochloric acid (7.5ml) after being cooled to 0 ℃.Mixture Na
2SO
4Carry out vacuum-evaporation after the drying, desolvate to remove.Residue acetone coevaporation is suspended in the ether, stirs and obtains a kind of amorphous solid after 21 days, it is developed with anhydrous diethyl ether obtain 2.1g amorphous solid title compound after 16 hours.Calculated value C
23H
27NO
3HCl:C, 68.7%; H, 7.0%; N, 3.5%; Measured value: C, 68.1%; H, 7.1%; N, 3.6%.
1H-NMR(DMSO-d
6)δ4.52(s，2H)；7.23(s，1H)。
Example 7
(R)-1-(2-(2-(N-(2-methyl isophthalic acid-propyl group)-N-phenyl amino) oxyethyl group) ethyl)-3-piperidine carboxylic acid hydrochloride
With N-(2-methyl isophthalic acid-propyl group)-N-aniline (14.9g, 100mmol), sym-dichloroacetic anhydride (19.0g, 111mmol) and the mixture of water (100ml) 70 ℃ the heating 1 hour.Reaction mixture is poured in the frozen water (300ml), the pH of water is transferred to 2 with concentrated hydrochloric acid.The compound that collecting precipitation goes out obtains 11.3g 2-chloro-N-(2-methyl isophthalic acid-propyl group)-phenyl acetanilide,Phenacetylaniline after vacuum-drying.
(12.4g, (16.8g 150mmol), makes temperature keep below 70 ℃ simultaneously to add potassium tert.-butoxide in DMF 200mmol) (50ml) solution carefully toward ethylene glycol.The gained mixture at room temperature stirred 30 minutes, then with above-mentioned ethanamide (11.3g, DMF 50mmol) (5ml) solution once adds wherein, mixture at room temperature stirred 1.5 hours.The reaction mixture example is gone in frozen water (400ml), use methylene dichloride (2 * 50ml) extractions then.The organic phase MgSO that merges
4Drying obtains 12.5g2-(2-hydroxyl-oxethyl)-N-(2-methyl isophthalic acid-propyl group)-phenyl acetanilide,Phenacetylaniline through vacuum-evaporation except that after desolvating.
Anhydrous THF (20ml) is added drop-wise to lithium aluminium hydride, and (2.8g is 75mmol) in the suspension in dry toluene (16ml).(12.5g, dry toluene 50mmol) (5ml) solution make temperature keep below 75 ℃ simultaneously to splash into above-mentioned hydroxyethyl acetamide then.After dropwising, mixture was at room temperature stirred 1 hour.Carefully add entry (10ml), when heat release begins to go down, disposable adding salt of wormwood (10g).Mixture was stirred 15 minutes, filter then.(2 * 100ml) wash each phase of separating filtrate to filter cake with methylene dichloride.Organic phase MgSO
4Drying obtains 10.6g 2-(2-(N-(2-methyl isophthalic acid-propyl group)-N-phenyl amino) oxyethyl group) ethanol after vacuum-evaporation removes solvent.
With above-mentioned alcohol (10.6g, 45mmol), triethylamine (7.3ml, 53mmol) and the mixture of methylene dichloride (100ml) be cooled to-10 ℃, (3.3ml 42mmol), makes temperature keep below-5 ℃ simultaneously to splash into methylsulfonyl chloride.After dropwising, mixture was stirred 1 hour at 0 ℃, at room temperature stirred then 30 minutes.Reaction mixture with 0.1N hydrochloric acid (2 * 50ml), water (50ml) and salt solution (10ml) washs.Organic phase MgSO
4Drying obtains 13.4g 2-(2-(N-(2-methyl isophthalic acid-propyl group)-N-phenyl amino) oxyethyl group) ethyl methane sulfonate ester after vacuum-evaporation removes solvent.
With top methanesulfonates (13.4g, 43mmol), (R)-3-piperidine carboxylate (10.0g, 64mmol), Quilonum Retard (3.1g, 43mmol) and the mixture of isopropyl acetate (100ml) at room temperature stirred 16 hours, under refluxing, stirred 24 hours then.Reaction mixture is filtered, and vaporising under vacuum removes solvent from filtrate.Residue is dissolved in the methylene dichloride (100ml) dry (MgSO
4) back with column chromatography purification on silica gel (100g, normal heptane/ethyl acetate=4/1), obtain 8.0g (R)-1-2-(2-(N-(2-methyl isophthalic acid-propyl group)-N-phenyl amino)-oxyethyl group) ethyl)-the 3-piperidine carboxylate.
(8.0g adds trimethylchlorosilane (4.6g, dry toluene 42mmol) (10ml) solution in dry toluene 21mmol) (30ml) solution to above-mentioned ester.(1.7ml 42mmol), allows the gained crystalline mixture, obtains 6.2g (R)-1-(2-(2-(N-(2-methyl isophthalic acid-propyl group)-N-phenyl amino) oxyethyl group) ethyl)-3-piperidine carboxylate dihydrochloride to add methyl alcohol carefully.
Two hydrochloric acid of above-mentioned ester are suspended in the water (20ml), the pH of water are transferred to 14 with 9N sodium hydroxide.Mixture heating up was refluxed 30 minutes, and cool to room temperature transfers to 0 with concentrated hydrochloric acid with pH then.Water concentrates under vacuum then with normal heptane (50ml) washing.(2 * 50ml) extractions, vaporising under vacuum obtains 1.2g spumescence title compound after falling solvent to residue with methylene dichloride.
1H?NMR(DMSO-d
6)δ3.75(m，4H)。
Example 8
(R)-1-(2-(2-(N-(2-chloro-4-fluorophenyl)-N-(2-methyl isophthalic acid-propyl group) amino) oxyethyl group) ethyl)-3-piperidine carboxylic acid hydrochloride
With N-(2-chloro-4-fluorophenyl) ethanamide (25.0g, 133mmol), the mixture heating up of concentrated hydrochloric acid (25ml) and ethanol (50ml) refluxed 3 hours.Mixture is cooled to 0 ℃, allows its crystallization.The collecting precipitation thing, after vacuum-drying, obtain 20.0g chlorination 2-chloro-4-fluorophenyl ammonium.
(20.0g 11mmol) in water-soluble (250ml), transfers to 7.5 with 9N sodium hydroxide with the pH of water, adds the 2 Methylpropionic acid acid anhydride then with top ammonium chloride.Mixture heating up was refluxed 45 minutes, place on the ice bath then and cool off.The product that collecting precipitation goes out with ethanol/water (1: 1) recrystallization, obtains 21.0g N-(2-chloro-4-fluorophenyl)-2-methyl propanamide.
(19.9g, 92mmol) suspension in THF (200ml) places on the ice bath and cools off with above-mentioned propionic acid amide.(100ml, 100mmol) solution at room temperature stirred mixture 16 hours the THF of adding 1M borane then.Add methyl alcohol (50ml) carefully, then add 1N hydrochloric acid (50ml).Under vacuum, volume is concentrated to 50ml, adds entry (200ml), the pH of water is transferred to 10 with 2N sodium hydroxide.(3 * 100ml) extract the organic phase of merging 4N hcl as extraction agent to mixture with methylene dichloride.Be separated two, the pH of water transferred to 10, use methylene dichloride (2 * 100ml) extractions then with 6N sodium hydroxide.Organic phase water (50ml) washing, dry (MgSO
4).After removing solvent, vacuum-evaporation obtains 15.0g N-(2-chloro-4-fluorophenyl)-N-(2-methyl isophthalic acid-propyl group) amine.
With top amine (15.0g, 74mmol) and triethylamine (12.0g, 119mmol) solution in methylene dichloride (200ml) is cooled to-10 ℃, (11.3g 113mmol), makes temperature keep below 10 ℃ simultaneously to add chloro-acetyl chloride then carefully.Mixture was at room temperature stirred 1 hour.Reaction mixture is poured in the water (200ml), with methylene dichloride (2 * 100ml) extractions.Organic phase with 4 N hydrochloric acid (2 * 50ml), the washing of water (100ml) and saturated sodium bicarbonate aqueous solution (50ml), dry (MgSO
4).After removing solvent, vacuum-evaporation obtains 13.6g 2-chloro-N-(2-chloro-4-fluorophenyl)-N-(2-methyl isophthalic acid-propyl group) ethanamide.
With potassium tert.-butoxide (11.6g, 104mmol) and the mixture of ethylene glycol (140ml) stirred 0.5 hour, (13.6g, 52mmol), mixture was 90 ℃ of heating 2 hours for the acid amides above adding then.Add water (100ml), (3 * 100ml) extract the gained mixture with ethyl acetate.The organic phase water that merges (3 * 50ml) and salt solution (10ml) washing, drying (MgSO then
4).Obtain 17.4g N-(2-chloro-4-fluorophenyl)-N-(2-methyl isophthalic acid-propyl group)-2-(2-hydroxyl-oxethyl) ethanamide after removing solvent to vacuum-evaporation.
(17.2g is cooled to-5 ℃ under anhydrous THF (150ml) solution indifferent gas 57mmol) encloses, and (1.63g 43mmol), stirs the gained mixture 5 minutes to add sodium borohydride with above-mentioned ethanamide.(8.1g 57mmol), keeps temperature to be lower than 0 ℃ simultaneously to add boron trifluoride diethyl etherificate thing then carefully.Mixture stirred 1 hour at 0 ℃, at room temperature stirred then 16 hours, at last 50 ℃ of heating 1 hour.At room temperature add sodium borohydride (1.63g, 43mmol), holding temperature is lower than 30 ℃, add carefully boron trifluoride diethyl etherificate thing (7.08ml, 63mmol).Mixture at room temperature stirred 1 hour, was heated to 50 ℃ then, kept 30 minutes.Add methyl alcohol (20ml), water (20ml) and ethyl acetate (100ml), be separated two.(2 * 50ml) extract the organic phase MgSO of merging to water with ethyl acetate
4Dry.Vacuum-evaporation removes and desolvates, and residue is gone up at silica gel (150g, normal heptane/ethyl acetate, gradient 9/1-1/1) with column chromatography and purified, and obtains 10.0g 2-(2-(N-(2-chloro-4-fluorophenyl)-N-(2-methyl isophthalic acid-propyl group) amino) ethoxy ethanol.
With above-mentioned alcohol (9.7g, 34mmol), triethylamine (5.6ml, 41mmol) and the mixture of methylene dichloride (100ml) be cooled to-30 ℃, (time spent keeps temperature to be lower than-15 ℃ for 4.2g, anhydrous methylene chloride 37mmol) (10ml) solution to splash into methylsulfonyl chloride then.After dropwising, allow mixture be warmed to room temperature, add water (50ml).Organic phase water (50ml), 0.2N hydrochloric acid (2 * 25ml), water (2 * 25ml) and salt solution (10ml) washing, use MgSO then
4Dry.Obtain 12.5g 2-(2-(N-(2-chloro-4-fluorophenyl)-N-(2-methyl isophthalic acid-propyl group) amino) oxyethyl group) ethyl methane sulfonate ester through vacuum-evaporation except that after desolvating.
With top methanesulfonates (12.5g, 34mmol), (+)-(R)-3-piperidine carboxylate tartrate (13.8g, 45mmol), Quilonum Retard (10.0g, 135mmol) and the mixture heating up of isopropyl acetate (150ml) refluxed 4 days.Reaction mixture is filtered, and filter cake washs with ethyl acetate.The organic phase water (50ml) and saturated ammonium chloride (50ml) solution washing that merge.Obtain 13.1g (R)-1-(2-(2-(N-(2-chloro-4-fluorophenyl)-N-(2-methyl isophthalic acid-propyl group) amino) oxyethyl group) ethyl)-3-piperidine carboxylate through vacuum-evaporation except that after desolvating.
(13.1g 31mmol) is dissolved in the ethanol (50ml), adds 2N sodium hydroxide (50ml), and mixture heating up was refluxed 1 hour with top ester.With concentrated hydrochloric acid pH is transferred to 0 behind the cool to room temperature.(2 * 100ml) washings transfer to 2.5 with 1N sodium hydroxide with the pH of water to the gained mixture with methylene dichloride.Mixture is evaporated solvent under vacuum with methylene dichloride (100ml) extraction from organic phase.In residue, add acetone (50ml) and ether (50ml), allow crystalline mixture.Obtain the 5.8g title compound.
1H?NMR(DMSO-d
6)δ3.75(2H，dd)。
Example 9
(R)-1-(2-(2-(2-benzyl phenyl) oxyethyl group) ethyl)-3-piperidine carboxylic acid hydrochloride
(24ml, 24mmol 1M) are added drop-wise in THF (100ml) solution of the 2-benzyl toluylic acid (5.5g, 24mmol, J.Am.Chem.Soc.1955,77,5078) that places on the ice bath with the THF solution of lithium aluminium hydride.After dropwising, mixture was at room temperature stirred 1 hour.Add entry (1ml), 4N sodium hydroxide (2ml) and water (4ml) successively.Mixture is filtered, and filtrate is diluted with ether (250ml).Separate two-phase, (MgSO is used in 3 * 100ml) washings to organic phase then with saturated ammonium chloride solution
4Dry.Obtain the thick 2-of 4.8g (2-benzyl phenyl) ethanol oily matter through vacuum-evaporation except that after desolvating.
With potassium hydroxide (2.6g, 46mmol) join the alcohol for preparing above (4.8g, 23mmol), (9.6g is 46mmol) and in the mixture of methyl-sulphoxide (100ml) for 2-bromotrifluoromethane tetrahydrochysene-2-pyranyl ether.Reaction mixture at room temperature stirred 20 hours, then 100 ℃ of heating 3 hours.Allow reaction mixture cool off, be poured into then in the frozen water (200ml), with ether (2 * 150ml) extractions.With the organic extract drying (MgSO that merges
4), after removing solvent, vacuum-evaporation obtains 4.6g oily residue.This oily matter (is carried out column chromatography and purifies, make elutriant with the mixed solution of heptane and ethyl acetate (1/4), obtain 1.3g 2-(2-(2-benzyl phenyl) oxyethyl group) ethanol oily matter at silica gel on 3 * 40cm).
(1.3g 6.1mmol) is dissolved in the methylene dichloride (50ml), adds triethylamine (10ml) then with top alcohol.At room temperature splash into methylsulfonyl chloride (0.77g, 6.7mmol).After dropwising, (3 * 50ml) wash reaction mixture, dry then (MgSO with methylene dichloride (100ml) dilution, water
4).The residue that obtains after vacuum-evaporation removes solvent is dissolved in the acetone (100ml).In this solution, add (R)-3-piperidine carboxylate tartrate (2.8g, 9.5mmol) and salt of wormwood (2.1 g, 15.3mmol), with this mixture heating up backflow 72 hours.(1.4g 4.8mmol), and continues heating 24 hours to add another part (R)-3-piperidine carboxylate tartrate again.Allow mixture cool off, with its filtration.(carry out column chromatography on 3 * 30cm) purifies the residue that obtains after vacuum-evaporation removes solvent at silica gel, heptane and ethyl acetate (1/1-3/7) with gradient are made elutriant, obtain 0.9g (R)-1-(2-(2-(2-benzyl phenyl) oxyethyl group) ethyl)-3-piperidine carboxylate oily matter.
(0.8g 2mmol) is dissolved in adding 2N sodium hydroxide (2ml) in the ethanol (10ml) with top ester.Mixture at room temperature stirred 20 hours, and vacuum-evaporation removes ethanol.Residue water (5ml) dilution is washed with ether.Aqueous phase in alkalescence adds concentrated hydrochloric acid till showing strong acid reaction.(3 * 100ml) extract the organic extract MgSO of merging to the gained mixture with methylene dichloride
4Dry.The spumescence residue acetone crystallization that obtains after vacuum-evaporation removes solvent obtains 0.52g solid title compound.M.p.144-145 ℃. calculated value C
23H
29NO
3HCl:C, 68.4%; H, 7.5%; N, 3.5%; Measured value: C, 68.1%; H, 7.7%; N, 3.1%.
Example 10
(R)-1-(2-(3-benzyl benzyl amino) ethyl)-3-piperidine carboxylic acid hydrochloride
((15g 70mmol) in the suspension in THF (100ml), after dropwising, at room temperature stirred mixture 30 minutes, and reflux is 40 minutes then 1M) to splash into the 3-benzylbenzoic acid for 80ml, 80mmol with the THF solution of lithium aluminium hydride.Allow reaction mixture cool off, add entry (3ml), ether (100ml), 4N sodium hydroxide (6ml) and water (12ml) then successively.Mixture was stirred 30 minutes, filter, vacuum-evaporation removes solvent.Residue is dissolved in the toluene (200ml) dry then (MgSO
4) spend the night.After removing solvent, vacuum-evaporation obtains the thick 3-benzyl of 11.9g benzyl alcohol oily matter.
(11.9g, (16.2g 80mmol) at room temperature stirred mixture 1 hour after dropwising superincumbent alcohol, and reflux is 15 minutes then to drip thionyl bromide in toluene 60mmol) (50ml) solution.Allow reaction mixture be cooled to room temperature, use toluene (400ml) dilution then.The gained mixture with 5% sodium bicarbonate (2 * 150ml), water (150ml) washing, use MgSO then
4Dry.After removing solvent, vacuum-evaporation obtains the oily residue that 15.3g contains 3-benzyl bromotoluene.The hexane solution (36ml) of 2.5M n-Butyl Lithium splashed into place nitrogen to enclose no water glycol (120ml) on the ice bath down.After dropwising, mixture was stirred 30 minutes, the bromotoluene of-inferior property above the adding then adds hexanaphthene (30ml) for flushing usefulness, at room temperature reaction mixture stirred 72 hours then.Add water (200ml), (2 * 150ml) extract the gained mixture with ether.The organic extract MgSO that merges
4Drying, the residue that obtains after vacuum-evaporation removes solvent are carried out the column chromatography purification on silica gel (600ml), make elutriant with the mixture of heptane and ethyl acetate (3/2), obtain 8.0g 2-(3-benzyl benzyloxy) ethanol.
(5.0g 21mmol) is dissolved in the ether (100ml), adds triethylamine (7.3ml) with top alcohol.At room temperature splash into then the methylsulfonyl chloride that is dissolved in the ether (20ml) (3.5g, 31mmol).Dropwising the relief reaction mixture spends the night.Add water (50ml), mixture was stirred 10 minutes.Be separated organic phase MgSO with two
4Drying, the residue that obtains after vacuum-evaporation removes solvent are dissolved in the acetone (150ml).In this solution, add (R)-3-piperidine carboxylate tartrate (9.5g, 31mmol) and salt of wormwood (7.3g, 53mmol), then with mixture heating up backflow 96 hours.Allow mixture cool off, with acetone (150ml) dilution and filtration.The residue that obtains after vacuum-evaporation removes solvent carries out column chromatography and purifies on silica gel (500ml), mixture with heptane and ethyl acetate (1/1) is made elutriant, obtains 4.3g (R)-1-(2-(3-benzyl benzyloxy) ethyl)-3-piperidine carboxylate oily matter.
(4.2g 11mmol) is dissolved in the ethanol (20ml), adds 2N sodium hydroxide (16.3ml) with top ester.Mixture at room temperature stirred 16 hours, and vacuum-evaporation removes ethanol.Residue water (20ml) dilution adds concentrated hydrochloric acid until react acid (pH2).(2 * 100ml) extract the organic extract MgSO of merging to the gained mixture with methylene dichloride
4Dry.Remove solvent through vacuum-evaporation and obtain the spumescence residue, with its crystallization, obtain 2.7g solid title compound with acetone.M.p.135-137 ℃. calculated value C
22H
27NO
3HCl:C, 67.8%; H, 7.2%; N, 3.6%; Measured value: C, 68.0%; H, 7.4%; N, 3.3%.
Example 11
(R)-1-(2-(2-(biphenyl-2-yl) oxyethyl group) ethyl)-3-piperidine carboxylic acid hydrochloride
(20.0g, THF 86mmol) (85ml) solution splash into magnesium, and (2.1g is 86mmol) in the backflow suspension in THF (15ml) with the 2-bromo biphenyl.With reaction mixture refluxed 18 hours, add again another batch 2-bromo biphenyl (2.0g, 8.6mmol).Reaction mixture refluxed 2 hours is cooled to 0 ℃ on ice bath.Adding oxyethane (14.0g, 0.32mol).Reaction mixture refluxed 18 hours is cooled to 0 ℃, drips ammonium chloride saturated solution (100ml) under this temperature.Reaction mixture adds concentrated hydrochloric acid and reaches 2 up to pH with ether (100ml) dilution.Separate organic phase, use MgSO
4Drying, vacuum concentration.Residue is carried out column chromatography purify on silica gel (800ml), make elutriant, obtain 8.5g 2-(biphenyl-2-yl) ethanol oily matter with heptane and ethyl acetate (7: 3).
With the alcohol for preparing above (8.5g, 43mmol), 2-bromotrifluoromethane tetrahydrochysene-2-pyranyl ether (17.9g, 86mmol) and potassium hydroxide (9.6g, 171mmol) mixture in methyl-sulphoxide (100ml) at room temperature stirred 72 hours.(3.6g, 17mmol), mixture at room temperature stirred 48 hours to add another batch 2-bromotrifluoromethane tetrahydrochysene-2-pyrans ether.Add water (350ml), (2 * 250ml) extract mixture with ether.Organic phase is merged, and MgSO is used in water (100ml) washing
4Drying, and carry out vacuum concentration.Residue carries out column chromatography on silica gel (400ml) purifies, and makes elutriant with heptane and ethyl acetate (3: 2), obtains 6.6g 2-(2-(biphenyl-2-yl) oxyethyl group) ethanol oily matter.
With methylsulfonyl chloride (4.7g, ether 41mmol) (20ml) drips of solution be added to the alcohol for preparing above (6.6g, 27mmol) and triethylamine (6.9g is 67mmol) in the solution in anhydrous diethyl ether (80ml).Reaction mixture at room temperature stirred 3 hours, with ether (50ml) dilution.Add water (100ml), MgSO is used in organic phase water (50ml) washing then
4Drying, and carry out vacuum concentration.Residue is dissolved in the acetone (150ml), add (R)-3-piperidine carboxylate tartrate (12.6g, 41mmol) and salt of wormwood (9.4g, 68mmol).With reaction mixture refluxed 6 days,, filter, and carry out vacuum concentration with acetone (100ml) dilution.Residue carries out chromatogram on silica gel (500ml) purifies, and makes elutriant with heptane and ethyl acetate (1: 3), obtains 6.0g (R)-1-(2-(2-(biphenyl-2-yl) oxyethyl group) ethyl)-3-piperidine carboxylate oily matter.
(6.0g, 16mmol are dissolved in the ethanol (30ml), add 2N sodium hydroxide (1.3ml) with top ester.Mixture at room temperature stirred 18 hours, removed ethanol then under vacuum.Residue transfers to pH2 with concentrated hydrochloric acid (6ml), uses methylene dichloride (2 * 150ml) extractions then.With organic phase merging, dry (MgSO
4), and carry out vacuum concentration.Residue obtains 4.7g white solid title compound with acetone (30ml) crystallization.M.p.122-124 ℃. calculated value C
22H
27N
1O
3HCl:C, 67.8%; H, 7.2%; N, 3.6%; Measured value: C, 67.9%:H, 7.3%; N, 3.5%.
Claims (9)
1. the compound of following general formula I or its pharmaceutically acceptable salt:
Wherein A is
Wherein:
R
1Be saturated or unsaturated 5 yuan or 6 yuan of carbocyclic rings, this carbocyclic ring can be randomly by the C of 1 or 2 halogens, straight or branched
1-4The C that alkyl, phenyl, phenyl replace
1-4The C that alkyl or phenyl replaces
2-4Alkenyl replaces, and described phenyl can be randomly by halogen, C
1-4Alkyl, C
1-4Alkoxyl group or trifluoromethyl replace, and these saturated or unsaturated 5 yuan or 6 yuan of carbocyclic rings can randomly condense with a phenyl ring;
R
2Be hydrogen, straight or branched C
1-8Alkyl, straight or branched C
2-8The C that alkenyl, phenyl, phenyl replace
1-4The C that alkyl or phenyl replaces
2-4Alkenyl, described phenyl can be randomly by halogen, C
1-4Alkyl, C
1-4Alkoxyl group or trifluoromethyl replace;
R
3And R
4Represent hydrogen separately or lump together and represent a key;
X is hydroxyl or C
1-4Alkoxyl group;
N is 0,1 or 2;
M is 2,3 or 4;
Its condition is: when A is
The time, R
1And R
2Must not be simultaneously for randomly by halogen, C
1-4Alkyl, C
1-4The phenyl that alkoxyl group or trifluoromethyl replace.
2. according to the compound of claim 1, this compound is:
1-(2-(3-phenyl-1-propoxy-) ethyl)-3-piperidine carboxylic acid;
(R)-1-(2-(2-benzyl benzyloxy) ethyl)-3-piperidine carboxylic acid;
(R)-1-(2-((1-phenyl-2-naphthyl) methoxyl group) ethyl)-3-piperidine carboxylic acid;
(R)-1-(2-(2-phenyl benzyloxy) ethyl)-3-piperidine carboxylic acid;
E-(R)-1-(2-((2,3-phenylbenzene-2-propylene-1-yl) oxygen) ethyl)-3-piperidine carboxylic acid;
Z-(R)-1-(2-((2,3-phenylbenzene-2-propylene-1-yl) oxygen) ethyl)-3-piperidine carboxylic acid;
(R)-1-(2-((2-(N-(2-methyl isophthalic acid-propyl group) N-phenyl amino) oxyethyl group) ethyl)-3-piperidine carboxylic acid;
(R)-1-(2-(2-(N-(2-chloro-4-fluorophenyl)-N-(2-methyl isophthalic acid-propyl group) amino) oxyethyl group) ethyl)-3-piperidine carboxylic acid;
(R)-1-(2-(2-(2-benzyl phenyl) oxyethyl group) ethyl)-3-piperidine carboxylic acid;
(R)-1-(2-(3-benzyl benzyloxy) ethyl)-3-piperidine carboxylic acid;
(R)-1-(2-(2-(biphenyl-2-yl) oxyethyl group) ethyl)-3-piperidine carboxylic acid;
Or the pharmaceutically acceptable salt of these compounds.
3. according to the preparation method of the compound of claim 1, it is characterized in that:
A) compound of formula II and the compound of formula III are reacted:
A-(CH
2)n-O-(CH
2)m-Y???????????(II)
A, n, m, R in formula II and the formula III
3, R
4With the definition of X as mentioned above, Y is a leavings group; Or
B) compound of formula IV and the compound of formula V are reacted:
A-(CH
2)n-OH???????????????????(IV)
More than A, n, R in two formulas
3, R
4, X and m definition as mentioned above, Z is a leavings group; Or
C) make the compound hydrolysis of formula I:
(wherein A, R
3, R
4, n and m definition as mentioned above, X is C
1-4Alkoxyl group), obtains the compound of formula I, wherein A, R
3, R
4, n and m definition as mentioned above, X is a hydroxyl.
4. be the pharmaceutical composition that activeconstituents contains pharmaceutically acceptable carrier or thinner simultaneously with compound according to claim 1.
5. contain the claim 1 of significant quantity compound and pharmaceutically acceptable carrier or thinner, be applicable to that treatment and GABA absorb the pharmaceutical composition of relevant central nervous system disorder.
6. according to the pharmaceutical composition of claim 4 or 5, wherein every dosage unit contains the compound of 0.5mg～1000mg according to claim 1.
7. the method that the patient of needs treatments is carried out absorbing with GABA the treatment of relevant central nervous system disorder comprises the compound according to claim 1 of described patient being used significant quantity.
8. the patient of needs treatments is carried out the method for the treatment of the central nervous system disorder relevant, comprise described patient is used pharmaceutical composition according to claim 5 with the GABA picked-up.
9. be used to prepare the purposes of the medicament for the treatment of the central nervous system disorder relevant with the GABA picked-up according to the compound of claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK0746/93 | 1993-06-23 | ||
| DK93746A DK74693D0 (en) | 1993-06-23 | 1993-06-23 | NOVEL HETEROCYCLIC CHEMISTRY |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1128989A true CN1128989A (en) | 1996-08-14 |
Family
ID=8097063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94193058A Pending CN1128989A (en) | 1993-06-23 | 1994-06-22 | N-substituted azaheterocylic carboxylic acid and esters thereof |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US5604242A (en) |
| EP (1) | EP0705248A1 (en) |
| JP (1) | JPH08511783A (en) |
| CN (1) | CN1128989A (en) |
| AU (1) | AU7067794A (en) |
| BG (1) | BG100246A (en) |
| CA (1) | CA2165946A1 (en) |
| CZ (1) | CZ335495A3 (en) |
| DK (1) | DK74693D0 (en) |
| FI (1) | FI956177A (en) |
| HU (1) | HUT75303A (en) |
| IL (1) | IL110078A0 (en) |
| NO (1) | NO955263L (en) |
| SK (1) | SK162795A3 (en) |
| WO (1) | WO1995000486A1 (en) |
| ZA (1) | ZA944470B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003097023A1 (en) * | 2002-05-21 | 2003-11-27 | Shanghai Institutes For Biological Sciences, Cas | The use of the inhibitor transmitter of ϝ-aminobutyric acid (gaba) in the manufacture of analgesic |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4549452B2 (en) * | 1997-12-12 | 2010-09-22 | 富山化学工業株式会社 | Alkyl ether derivatives or salts thereof and calcium antagonists containing them |
| WO1999031056A1 (en) * | 1997-12-12 | 1999-06-24 | Toyama Chemical Co., Ltd. | Alkyl ether derivatives or salts thereof and calcium antagonists containing the same |
| KR100956990B1 (en) | 2001-10-19 | 2010-05-11 | 토야마 케미칼 컴퍼니 리미티드 | Alkyl Ether Derivatives or Salts Thereof |
| MXPA05011125A (en) | 2003-04-17 | 2005-12-14 | Toyama Chemical Co Ltd | Preventive/remedy for retinal nerve diseases containing alkyl ether derivatives or salts thereof. |
| MXPA06014026A (en) * | 2004-07-02 | 2007-02-08 | Warner Lambert Co | Compositions and methods for treating pathological infections. |
| DE102006053500A1 (en) * | 2006-11-14 | 2008-05-15 | Evonik Goldschmidt Gmbh | Antimicrobial compounds for controlling selective microorganisms such as gram-positive bacteria, particularly coryneform bacteria, has general formula |
| US20120305840A1 (en) * | 2009-09-24 | 2012-12-06 | Kabushiki Kaisha Toshiba | Carbon dioxide absorbing solution |
| AU2018210393A1 (en) | 2017-01-20 | 2019-07-25 | The Regents Of The University Of California | Inhibitors of the N-terminal domain of the androgen receptor |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4910312A (en) * | 1985-11-08 | 1990-03-20 | Warner-Lambert Company | Various N-substituted 3-piperidine carboxylic acids or N-substituted 3-pyridinecarboxylic acids and derivatives thereof |
| DK588189D0 (en) * | 1989-11-22 | 1989-11-22 | Novo Nordisk As | NEW HETEROCYCLIC CARBOXYLIC ACIDS |
| DK93791D0 (en) * | 1991-05-17 | 1991-05-17 | Novo Nordisk As | NEW HETEROCYCLIC CARBOXYLIC ACIDS |
-
1993
- 1993-06-23 DK DK93746A patent/DK74693D0/en not_active Application Discontinuation
-
1994
- 1994-06-21 IL IL11007894A patent/IL110078A0/en unknown
- 1994-06-22 US US08/263,641 patent/US5604242A/en not_active Expired - Fee Related
- 1994-06-22 CZ CZ953354A patent/CZ335495A3/en unknown
- 1994-06-22 JP JP7502353A patent/JPH08511783A/en active Pending
- 1994-06-22 CA CA002165946A patent/CA2165946A1/en not_active Abandoned
- 1994-06-22 SK SK1627-95A patent/SK162795A3/en unknown
- 1994-06-22 WO PCT/DK1994/000253 patent/WO1995000486A1/en not_active Application Discontinuation
- 1994-06-22 EP EP94919562A patent/EP0705248A1/en not_active Withdrawn
- 1994-06-22 ZA ZA944470A patent/ZA944470B/en unknown
- 1994-06-22 CN CN94193058A patent/CN1128989A/en active Pending
- 1994-06-22 AU AU70677/94A patent/AU7067794A/en not_active Abandoned
- 1994-06-22 HU HU9503755A patent/HUT75303A/en unknown
-
1995
- 1995-12-21 FI FI956177A patent/FI956177A/en unknown
- 1995-12-21 BG BG100246A patent/BG100246A/en unknown
- 1995-12-22 NO NO955263A patent/NO955263L/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003097023A1 (en) * | 2002-05-21 | 2003-11-27 | Shanghai Institutes For Biological Sciences, Cas | The use of the inhibitor transmitter of ϝ-aminobutyric acid (gaba) in the manufacture of analgesic |
Also Published As
| Publication number | Publication date |
|---|---|
| HUT75303A (en) | 1997-05-28 |
| HU9503755D0 (en) | 1996-02-28 |
| IL110078A0 (en) | 1994-10-07 |
| SK162795A3 (en) | 1996-09-04 |
| NO955263D0 (en) | 1995-12-22 |
| EP0705248A1 (en) | 1996-04-10 |
| WO1995000486A1 (en) | 1995-01-05 |
| BG100246A (en) | 1996-07-31 |
| AU7067794A (en) | 1995-01-17 |
| CA2165946A1 (en) | 1995-01-05 |
| CZ335495A3 (en) | 1996-07-17 |
| DK74693D0 (en) | 1993-06-23 |
| JPH08511783A (en) | 1996-12-10 |
| FI956177A (en) | 1996-02-21 |
| ZA944470B (en) | 1995-12-22 |
| US5604242A (en) | 1997-02-18 |
| NO955263L (en) | 1996-02-22 |
| FI956177A0 (en) | 1995-12-21 |
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| C06 | Publication | ||
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| SE01 | Entry into force of request for substantive examination | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |